The compounds of the present invention are useful in the treatment of diseases or pathological conditions in which endothelial dysfunction is known to be a pathogenic and/or aggravating mechanism. Such pathologies are: atherosclerosis, the existence of vascular risk factors (dyslipidaemia, diabetes, systemic arterial hypertension), the various clinical forms of myocardial or peripheral ischaemia, cardiac insufficiency and the various forms of pulmonary arterial hypertension. The said compounds are also useful in the treatment of patients undergoing heart transplantation or vascular repermeabilisation such as a bypass, thrombolysis or arterial dilatation with or without a stent.
A reduction in the vascular availability of nitrogen monoxide (NO) constitutes the major mechanism of endothelial dysfunction observed in the diseases and pathological conditions mentioned above and explains its pathogenic role (Cardiovasc. Res., 1999, 43, 572; Coronary. Art. Dis. 1999, 10, 277; Coronary. Art. Dis., 1999, 10, 301; Coronary. Art. Dis., 1999, 10, 287; Coronary. Art. Dis., 1999, 10, 295).
In the said pathological conditions, the endothelial dysfunction may in fact result from two main mechanisms: 1) inadequate production of NO associated with inhibition of endothelial NO synthase by endogenous inhibitors such as ADMA (asymmetric dimethyl-arginine), the plasma concentration of which increases in patients exhibiting cardiovascular risk factors (Cardiovasc. Res., 1999, 43, 542; Hypertension, 1997, 29, 242; Circulation, 1997, 95, 2068), 2) inactivation of the NO by the superoxide anion (O2xe2x88x92), the production of which is increased in pathological conditions (Cardiovasc. Res., 1999, 43, 562; Eur.J Biochem. 1997, 245, 541; J Clin. Invest., 1993, 91 2546).
Under normal conditions, NO produces major effects such as : 1) regulation of arterial vasomotricity by means of its vasodilator effect (N Engl. J Med, 1993, 329, 2002; Nature, 1980, 288, 373), 2) limitation of platelet adhesion and aggregation (Trends Pharmacol. Sci., 1991, 12, 87), 3) control of the adhesion of leukocytes and monocytes to endothelial cells (Proc. Natl Acad Sci. USA, 1991, 88, 4651), 4) inhibition of the proliferation of vascular smooth muscle cells (Cardiovasc. Res., 1999, 43, 580, Circulation, 1993, 87 V51), which explains why the deficiency of NO in the arterial wall is favourable to pathological phenomena such as vasoconstriction, thrombosis, lipid accumulation and proliferation of vascular smooth muscle cells.
In vitro experiments have enabled it to be shown that the compounds of the present invention are capable of limiting the endothelial dysfunction and reduced vascular availability of NO that are caused by tests involving the two physiopathological mechanisms already mentioned: inhibition of endothelial NO synthase and oxidative stress due to production of O2xe2x88x92.
Besides the fact that they are new, the compounds of the present invention, by virtue of their specific pharmacological activity, which is capable of limiting the development of endothelial dysfunction, are useful in preventing the development, extension and complications of atherosclerotic lesions, especially in patients exhibiting a vascular risk factor (dyslipidaemia, diabetes, arterial hypertension), and in treating the various clinical forms of myocardial or peripheral ischaemia, cardiac insufficiency and the various forms of pulmonary arterial hypertension. The compounds are also used for preventing vascular complications (spasm, thrombosis, restenosis, accelerated atherosclerosis) in patients undergoing a bypass, vascular dilatation with or without a stent or other forms of vascular repermeabilisation and also heart transplantation.
Compounds of similar structure have been described in the literature, that being the case, more especially, for Patent Application WO 94/13659, which claims compounds containing especially a cyclic urea structure, those compounds being useful in the treatment of diseases of the central nervous system such as depression or psychosis. Similarly, Patent Specification FR 2 338 940 describes compounds containing especially a 1-{1-[2-hydroxy-3-(aryloxy)-propyl]-4-piperidyl}-3-aryl-imidazolidin-2-one structure and claims them for their usefulness in the treatment of vascular hypertension. Finally, Patent Specification EP 0 526 342 describes new (isoquinolin-5-yl)sulphonamides. which are useful in the treatment of myocardial ischaemia.
The compounds of the present invention are clearly distinguished from that prior art, both in their particular chemical structure and in their specific pharmacological activity of endothelial protection.
More specifically, the present invention relates to compounds of formula (I): 
wherein:
V represents a single bond or a linear or branched (C1-C6)alkylene chain,
M represents a single bond or a linear or branched (C1-C6)alkylene chain,
A and E each represents a nitrogen atom or a CH group, but at least one of the two groups A or E represents a nitrogen atom,
W represents a group of formula (i) or (ii), and also may represent a group of formula (iii) but only when V represents a single bond and A represents a nitrogen atom,
in which groups of formulae (i), (ii) and (iii): 
X represents a carbonyl, sulphonyl or sulphoxide group,
G1 represents a linear (C2-C4)alkylene chain optionally containing a double bond and/or being optionally substituted by a hydroxyl group,
G2 represents a single bond or a methylene group,
G3 represents:
a linear (C2-C3)alkylene chain when G2 represents a bond,
or a linear (C1-C2)alkylene chain when G2 represents a methylene group, the said alkylene chain in each of those cases optionally containing a double bond,
T represents a phenyl group fused with the ring to which it is attached or a pyridyl group fused with the ring to which it is attached,
R1 represents a hydrogen atom, a linear or branched (C1-C6)alkyl group, an aryl group or an aryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched,
R2a and R2b, which are the same or different, each independently of the other represents a group selected from a hydrogen atom, a halogen atom, a linear or branched (C1-C6)alkyl group, a hydroxy group, a linear or branched (C1-C6)alkoxy group, a mercapto group, a linear or branched (C1-C6)alkylthio group, a linear or branched (C1-C6)trihaloalkyl group, a cyano group, a nitro group, an amino group, a linear or branched (C1-C6)alkylamino group, a di-(C1-C6)alkylamino group in which each alkyl moiety may be linear or branched, a linear or branched (C1-C6)trihaloalkoxy group, an aryloxy group, an aryl-(C1-C6)alkoxy group in which the alkoxy moiety is linear or branched, a linear or branched (C1-C6)alkylsulphonate group, a linear or branched (C1-C6)trihaloalkylsulphonate group and a linear or branched (C1-C6)-alkylsulphonyl group,
or R2a+R2b, taken together in adjacent positions, represent a group selected from methylenedioxy, 1,2-ethylenedioxy, 1,3-propylenedioxy, and ethylene optionally substituted by a group selected from cyano, hydroxymethyl, linear or branched (C1-C6)alkoxycarbonyl, aryloxycarbonyl and aryl-(C1-C6)alkoxycarbonyl in which the alkoxy moiety is linear or branched,
R3 represents an aryl or heteroaryl-A group, each of which groups may optionally be substituted by one or more groups, which may be the same or different, selected from among the definitions of R2a,
Y represents an aryloxy, heteroaryloxy or heteroaryl-B group, each of which groups may optionally be substituted by one or more groups, which may be the same or different, selected from among the definitions of R2a,
their isomers, their hydrates, their solvates and addition salts thereof with a pharmaceutically acceptable acid,
wherein:
an aryl group is understood to mean a group selected from phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indanyl, indenyl and benzocyclobutyl,
a heteroaryl-A group is understood to mean a monocyclic aromatic or bicyclic. 5- to 12-membered system containing one or two hetero atoms, which may be the same or different, selected from oxygen, nitrogen and sulphur, and wherein, in the case of a bicyclic system, one of the rings has an aromatic character and the other ring may be aromatic or partially hydrogenated,
a heteroaryl-B group is understood to mean a monocyclic aromatic or bicyclic aromatic, 5- to 12-membered system containing from 1 to 3 hetero atoms, which may be the same or different, selected from oxygen, nitrogen and sulphur,
an aryloxy group is understood to mean an aryl group as defined hereinbefore attached to an oxygen atom,
a heteroaryloxy group is understood to mean a heteroaryl-A group as defined hereinbefore attached to an oxygen atom,
with the proviso that:
when V represents a single bond and W represents a group of formula (i) wherein R3 represents a phenyl group, then Y cannot represent a 3-indolyl group,
when M represents a single bond and W represents a group of formula (i), then if Y represents a bicyclic heteroaryl-B group wherein one of the rings represents a benzene ring the said group Y cannot be joined to M by the said benzene ring,
and when M represents a single bond, V represents an ethylene group and W represents a group of formula (i) wherein R3 represents a phenyl group, then Y cannot represent a 1,2-benzisoxazol-3-yl group.
Among the pharmaceutically acceptable acids there may be mentioned, without implying any limitation, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulphonic acid, camphoric acid etc.
Preferred substituents Y according to the invention are the benzofuran-3-yl group and the phenyloxy group optionally substituted by a group R2a as defined for formula (I).
A preferred substituent X according to the invention is the carbonyl group.
According to an advantageous embodiment of the invention, preferred compounds are compounds of formula (I) wherein W represents a group of formula (I) as defined for formula (I).
Especially advantageously, preferred compounds of the invention are compounds of formula (IA): 
wherein:
R3 represents an aryl group, and advantageously a phenyl group, optionally substituted by a group selected from a halogen atom, a hydroxy group, a linear or branched (C1-C6)-alkoxy group, an aryl-(C1-C6)alkoxy group in which the alkoxy moiety is linear or branched, a nitro group, a linear or branched (C1-C6)trihaloalkyl group and a cyano group,
X represents a carbonyl group,
G1 represents a linear (C2-C3)alkylene chain,
V is as defined for formula (I),
A represents a nitrogen atom when E represents a CH group, or
A represents a CH group when E represents a nitrogen atom,
M represents a linear or branched (C1-C4)alkylene chain,
Y represents a benzofuran-3-yl group, or a phenyloxy group optionally substituted by a group selected from a halogen atom, a linear or branched (C1-C6)alkylsulphonyl group and a linear or branched (C1-C6)alkylthio group.
In a very preferable manner, preferred compounds of the invention are compounds of formula (IA) as defined hereinbefore wherein:
A represents a nitrogen atom and E represents a CH group when Y represents an optionally substituted phenyloxy group,
or A represents a CH group and E represents a nitrogen atom when Y represents a benzofuran-3-yl group.
In another preferable manner, preferred compounds of the invention are compounds of formula (IA) as defined hereinbefore wherein V represents a single bond when Y represents a benzofuran-3-yl group and V represents a linear or branched (C1-C4)alkylene chain when Y represents an optionally substituted phenyloxy group.
According to another advantageous embodiment of the invention, preferred compounds are compounds of formula (I) wherein W represents a group of formula (ii) as defined for formula (I).
Especially advantageously, preferred compounds of the invention are compounds of formula (IB): 
wherein:
R2a and R2b are as defined for formula (I),
G3 represents a group of formula xe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)3xe2x80x94 or xe2x80x94CHxe2x95x90CHxe2x80x94,
X represents a carbonyl group,
R1 represents a hydrogen atom,
A, E and V are as defined for formula (I),
M represents a linear or branched (C1-C4)alkylene chain,
Y represents a benzofuran-3-yl group, or a phenyloxy group optionally substituted by a group selected from a halogen atom, a linear or branched (C1-C6)alkylsulphonyl group and a linear or branched (C1-C6)alkylthio group.
In a very preferable manner, preferred compounds of the invention are compounds of formula (IB) as defined hereinbefore wherein:
A represents a nitrogen atom and E represents a CH group when Y represents an optionally substituted phenyloxy group,
or A represents a CH group and E represents a nitrogen atom when Y represents a benzofuran-3-yl group.
In another preferable manner, preferred compounds of the invention are compounds of formula (IB) as defined hereinbefore wherein V represents a single bond when Y represents a benzofuran-3-yl group and V represents a linear or branched (C1-C4)alkylene chain when Y represents an optionally substituted phenyloxy group.
According to a third advantageous embodiment of the invention, preferred compounds are compounds of formula (I) wherein W represents a group of formula (iii) as defined for formula (I).
Especially advantageously, preferred compounds of the invention are compounds of formula (IC): 
wherein:
R2a, R2b and M are as defined for formula (I),
G3 represents a group of formula xe2x80x94(CH2)2xe2x80x94,
X represents a carbonyl group,
Y represents a benzofuran-3-yl group, or a phenyloxy group optionally substituted by a group selected from a halogen atom and a linear or branched (C1C6)alkylsulphonyl group.
Preferred compounds of the invention are:
N-{2-[4-(phenoxymethyl)-1-piperidyl]ethyl}1indolinecarboxamide,
5-fluoro-N-(2-{4-[2-(4-fluorophenoxy)ethyl]-1-piperidyl}ethyl)-1-indolecarboxamide,
N-{2-[4-p-fluorophenoxymethyl)-1-piperidyl]ethyl}1-indolinecarboxamide,
N-{2-[4-(phenoxymethyl)-1-piperidyl]ethyl}-1-indolecarboxamide,
and 1-(2-{4-[2-(4-fluorophenoxy)ethyl]-1-piperidyl}ethyl)-3-phenyl-2-imidazolidinone.
The isomers, as well as the hydrates, solvates and addition salts with a pharmaceutically acceptable acid, of the preferred compounds form an integral part of the invention.
The invention relates also to a process for the preparation of compounds of formula (I), which process is characterised in that there is used as starting material
a compound of formula (II):
R3xe2x80x94Nxe2x95x90Cxe2x95x90Oxe2x80x83xe2x80x83(II),
wherein R3 is as defined for formula (I),
which is reacted
with a compound of formula (III):
HOxe2x80x94G1axe2x80x94NHxe2x80x94Vaxe2x80x94OHxe2x80x83xe2x80x83(III),
wherein Va represents a (C2-C6)alkylene chain and G1a represents a linear (C2-C3)alkylene chain,
to yield the compounds of formula (IVa): 
wherein R3, G1a and Va are as defined hereinbefore,
which compounds of formula (IVa) are converted by conventional methods of organic synthesis to yield the compounds of formula (IVb): 
wherein P1 represents a chlorine, bromine or iodine atom or a group OSO2R4 wherein R4 represents a methyl, trifluoromethyl or tolyl group, and R3, Va and G1a are as defined hereinbefore,
which compounds of formula (IVb) are subjected to the action of heat to yield the compounds of formula (IVc): 
wherein R3, G1a, Va and P1 are as defined hereinbefore, which compounds of formula (IVc) are treated under basic conditions with a compound of formula (V): 
wherein E, M and Y are as defined for formula (I),
to yield the compounds of formula (I/a), a particular case of the compounds of formula (I): 
wherein R3, G1a, Va, E, M and Y are as defined hereinbefore,
or with a compound of formula (VI): 
wherein A, E, M and Y have the same meanings as in formula (I) and Vb represents a (C1-C6)alkylene chain,
to yield the compounds of formula (VII): 
wherein R3, Vb, A, E, M and Y are as defined hereinbefore,
which compounds of formula (VII) are treated in the presence of a strong base with a compound of formula (VIII):
P1xe2x80x94G1bxe2x80x94Pxe2x80x21xe2x80x83xe2x80x83(VIII),
wherein P1 and Pxe2x80x21, which are the same or different, are as defined for P1 hereinbefore and G1b represents a C4alkylene chain optionally containing a double bond,
to yield the compounds of formula (I/b), a particular case of the compounds of formula (I): 
wherein R3, G1b, Vb, A, E, M and Y are as defined hereinbefore,
or with a compound of formula (IX): 
wherein G1c represents a linear C1- or C2-alkylene chain , R5 represents a linear or branched (C1-C6)alkyl group, and V, A, E, M and Y are as defined for formula (I),
to yield the compounds of formula (X): 
wherein R3, G1c, V, A, R5, M and Y are as defined hereinbefore, which compounds of formula (X) are placed in the presence of a strong organic acid to yield the compounds of formula (I/c), a particular case of the compounds of formula (I): 
wherein R3, G1c, V, A, E, M and Y are as defined hereinbefore, which compound of formula (I/c) is hydrogenated according to conventional techniques of organic synthesis to yield the compounds of formula (I/d), a particular case of the compounds of formula (I): 
wherein R3, G1c, V, A, E, M and Y are as defined hereinbefore,
or which compounds of formula (I/c) are dehydrated under conventional conditions of organic synthesis to yield the compounds of formula (I/e), a particular case of the compounds of formula (I): 
wherein R3, G1c, V, A, E, M and Y are as defined hereinbefore,
c or a compound of formula (IIa):
R3xe2x80x94NHxe2x80x94SO2Clxe2x80x83xe2x80x83(IIa),
wherein R3 is as defined for formula (I), which is reacted with a compound of formula (IIIa):
Halxe2x80x94G1axe2x80x94NHxe2x80x94VaHalxe2x80x83xe2x80x83(IIIa)
wherein Hal represents a halogen atom and G1a and Va have the same meanings as hereinbefore,
to yield the compounds of formula (IIIb): 
wherein R3, G1a, Va and Hal are as defined hereinbefore,
which compounds of formula (IIIb) are reacted to yield the compounds of formula (IIIc): 
wherein R3, G1a, Va and Hal are as defined hereinbefore,
which compounds of formula (IIIc) are treated under basic conditions with a compound of formula (V): 
wherein E, M and Y are as defined for formula (I),
to yield the compounds of formula (I/i), a particular case of the compounds of formula (I): 
wherein R3, G1a, Va, E. M and Y are as defined hereinbefore,
or a compound of formula (XV) 
wherein R2a, R2b, G2, G3 and T have the same meanings as in formula (I),
which compound of formula (XV) is treated either with diphosgene or triphosgene, in the presence of a base, or with di-(1H-imidazol-1-yl)methanone to yield the compounds of formula (XVI): 
wherein R2a, R2b, G2, G3 and T are as defined hereinbefore and Ra represents a chlorine atom, a 1H-imidazol-1-yl group or
a group of formula: 
wherein R2a, R2b, G2, G3 and T are as defined hereinbefore, which compound of formula (XVI) is reacted with a compound of formula (XVII): 
wherein R1, V, A, E, M and Y are as defined for formula (I), to yield the compounds of formula (I/f), a particular case of the compounds of formula (I): 
wherein R2a, R2b, G2, G3, T, R1, V, A, E, M and Y are as defined for formula (I),
or which compound of formula (XV) is treated under basic conditions with diphosgene, with triphosgene, with SO2Cl2, with SOCl2, with di-(1H-imidazol-1-yl)methanone or with di-(1H-imidazol-1-yl)sulphonyl,
to yield the compounds of formula (XVIII): 
wherein R2a, R2b, G2, G3, T and X have the same meanings as in formula (I) and Ra is as defined hereinbefore,
which compounds of formula (XVIII) are placed in the presence of a compound of formula (V) as described hereinbefore
to yield the compounds of formula (I/g), a particular case of the compounds of formula (I): 
wherein R2a, R2b, G2, G3, T, X, E, M and Y are as defined hereinbefore,
or finally which compound of formula (XV) is reacted with chlorosulphonyl isocyanate, in the presence of a compound of formula (XIX):
Halxe2x80x94V1xe2x80x94OHxe2x80x83xe2x80x83(XIX),
wherein V1 represents a linear (C2-C6)alkylene chain and Hal represents a chlorine, bromine or iodine atom,
to yield the compounds of formula (XX): 
wherein R2a, R2b, G2, G3, T and V1 are as defined hereinbefore,
which compound of formula (XX) is then treated in succession with an alkali metal hydroxide and then with carbon tetrabromide in the presence of triphenylphosphine
to yield the compounds of formula (XXI): 
wherein R2a, R2b, G2, G3, T and V1 are as defined hereinbefore,
which compounds of formula (XXI) are reacted with a compound of formula (V) as described hereinbefore,
to yield the compounds of formula (I/h), a particular case of the compounds of formula (I): 
wherein R2a, R2b, G2, G3, T, V1, E, M and Y are as defined hereinbefore,
the totality of the compounds of formulae (I/a) to (I/i) constituting the compounds of the invention, which are purified, if necessary, according to conventional purification techniques, are separated, where appropriate, into their isomers according to a conventional separation technique and are converted, if desired, into their hydrates, solvates or addition salts with a pharmaceutically acceptable acid.
The compounds of formulae (II), (III), (V), (VI), (VIII), (IX), (XV), (XVII) and (XIX) are either commercial products or are obtained according to known and conventional methods of organic synthesis.
The compounds of the present invention are useful in the treatment of diseases or pathological conditions in which endothelial dysfunction is known. Accordingly, by virtue of their specific pharmacological activity, the compounds of the invention are useful in preventing the development, extension and complications of atherosclerotic lesions, in particular for patients having a vascular risk factor (dyslipidaemia, diabetes, systemic arterial hypertension), in the treatment of myocardial or peripheral ischaemia, of cardiac insufficiency and of pulmonary arterial hypertension and in the prevention of vascular complications after vascular bypass, vascular dilatation, repermeabilisation and heart transplantation.
The present invention relates also to pharmaceutical compositions comprising as active ingredient at least one compound of formula (I), an optical isomer, hydrate, solvate or addition salt thereof with a pharmaceutically acceptable acid, alone or in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients or carriers.
Among the pharmaceutical compositions according to the invention there may be mentioned more especially those that are suitable for oral, parenteral (intravenous, intramuscular or sub-cutaneous), per- or trans-cutaneous, nasal, rectal, perlingual, ocular or respiratory administration, and especially tablets or dragees, sublingual tablets, soft gelatin capsules, hard gelatin capsules, suppositories, creams, ointments, dermal gels, injectable or drinkable preparations, aerosols, eye or nose drops etc . . .
The useful dosage varies according to the age and weight of the patient, the route of administration, the nature and severity of the disorder and any associated treatments taken, and ranges from 1 mg to 200 mg in one or more administrations per day.
The following Examples illustrate the invention but do not limit it in any way. The starting materials used are known products or are prepared according to known procedures. The different Preparations yield synthesis intermediates that are useful in preparation of the compounds of the invention.
The structures of the compounds described in the Examples were determined according to the usual spectrophotometric techniques (infrared, nuclear magnetic resonance, mass spectrometry, . . . ).
The melting points were determined using either a Kofler hot-plate (K.) or a hot-plate under a microscope (M.K.).
Step 1: N-tert-butyloxycarbonyl-4-(p-fluorophenoxymethyl)piperidine
Over the course of 30 minutes, 10.5 ml of diethyl azodicarboxylate are poured onto a mixture of 13.5 g of N-tert-butyloxycarbonyl-4-hydroxymethylpiperidine, 7.45 g of p-fluorophenol, 17.4 g of triphenylphosphine and 140 ml of tetrahydrofuran. After stirring for 12 hours at ambient temperature, the reaction mixture is concentrated, taken up in ether, washed with water and then 1N sodium hydroxide solution, and then washed with water. After drying, filtration and evaporation under reduced pressure, chromatography over silica gel (cyclohexane/ethyl acetate: 90/10) allows the expected product to be isolated.
Melting point (K): 94-98xc2x0 C.
Step 2: 4-(p-Fluorophenoxymethyl)piperidine
12.1 g of the product obtained in Step 1 are treated, at ambient temperature, with 300 ml of ethereal hydrogen chloride solution for 48 hours, allowing the title product to be obtained in the form of the hydrochloride. The free base is obtained by treating the hydrochloride with 1N sodium hydroxide solution followed by extraction with dichloromethane.
The product is obtained according to the procedure of Preparation 1 using 2-(N-tert-butyloxycarbonyl-4-piperidyl)ethanol as substrate in Step 1.
The product is obtained according to the procedure of Preparation 1 using phenol instead of p-fluorophenol in Step 1.
The product is obtained according to the procedure of Preparation 1 using p-methyl-sulphonylphenol instead of p-fluorophenol in Step 1.
Melting point (hydrochloride): 230-234xc2x0 C.
The product is obtained according to the procedure of Preparation 1 using 2-(N-tert-butyloxycarbonyl-4-piperidyl)ethanol and p-methylsulphonylphenol in Step 1.
Step 1: 1-tert-Butyloxycarbonyl-2-{4-[(4-methylsulphonylphenoxy)methyl]-1-piperidyl}ethylamine
11.1 mmol of the product of Preparation 4, 11.1 mmol of 1-tert-butyloxycarbonyl-2-bromoethylamine, 4.6 g of sodium carbonate and a spatula tip of potassium iodide are added to 50 ml of methyl isobutyl ketone. After 8 hours at reflux and then 12 hours at ambient temperature, a white solid is obtained which is recrystallised from acetonitrile, allowing the expected product to be isolated.
Step 2: 2-{4-[(4-Methylsulphonylphenoxy)methyl]-1-piperidyl}ethylamine
The procedure is as in Step 2 of Preparation 1.
Step 1: N-tert-butyloxycarbonyl-1-[2-(benzofuran-3-yl)ethyl]-4-piperidylamine
10 mmol of 2-(benzofuran-3-yl)-1-bromoethane, 9.62 mmol of tert-butyl 4-piperidyl-carbamate, 2.65 g of potassium carbonate and 0.65 g of tetrabutylammonium sulphate are added to 10 ml of toluene. After refluxing for 12 hours, the mixture is taken up in water. The organic phase is then washed with water, dried and then filtered. Evaporation under reduced pressure allows the expected product to be isolated.
The procedure is as in Step 2 of Preparation 1.
The product is obtained according to the procedure of Preparation 7 using 3-(benzofuran-3-yl)-1-bromopropane as substrate in Step 1.
12.3 mmol of the product of Preparation 7 and 12.3 mmol of glyoxal 1,1-dimethyl acetal as a 45% solution in tert-butyl methyl ether are added to 50 ml of dichloromethane. After reacting for 15 minutes, 18.45 mmol of sodium triacetoxyborohydride and then 0.69 ml of acetic acid are added. After 12 hours, the reaction mixture is poured onto 100 ml of 1N sodium hydroxide solution. The organic phase is then washed with water, dried and then filtered. Evaporation under reduced pressure allows the expected product to be obtained.
The product is obtained according to the procedure of Preparation 9 using the product of
Preparation 8 instead of that of Preparation 7 as substrate
The product is obtained according to the procedure of Preparation 9 using, as substrate, the product of Preparation 7 and 3-amino-propionaldehyde diethyl acetal.
The product is obtained according to the procedure of Preparation 9 using, as substrate, the product of Preparation 8 and 3-amino-propionaldehyde diethyl acetal.
84 mmol of 2-(benzofuran-3-yl)-1-bromoethane, 67 mmol of piperazine and 56 mmol of potassium carbonate are added to 200 ml of acetonitrile. After refluxing for 4 hours, the reaction mixture is cooled and then concentrated. The residue is taken up in dichloromethane, is washed with water, dried, filtered and then concentrated under reduced pressure. Chromatography over silica gel (dichloromethane/ethanol: 90/10) allows the expected product to be isolated.
The product is obtained according to the procedure of Preparation 13 using 3-(benzofuran-3-yl)-1-bromopropane as substrate.
The product is obtained according to the procedure of Preparation 13 using 1-bromo-2-(p-fluorophenoxy)ethane as substrate.
The product is obtained according to the procedure of Preparation 13 using 1-bromo-3-(p-fluorophenoxy)propane as substrate.
Step 1: {4-[2-(Fluorophenoxy)ethyl]-1-piperidyl}acetonitrile
92.4 mmol of the product of Preparation 2, 6.5 ml of bromoacetonitrile and 39.2 g of potassium carbonate are added to 320 ml of methyl isobutyl ketone. After refluxing for 12 hours, the reaction mixture is filtered and concentrated under reduced pressure. The residue is taken up in water and dichloromethane. The organic phase is washed with water, dried, filtered and then concentrated under reduced pressure, allowing the expected product to be obtained.
Melting point (K): 72xc2x0 C.
Step 2: 2-{4-[2-(p-Fluorophenoxy)ethyl]-1-piperidyl}ethylamine
A solution of the product obtained in Step 1 dissolved in 200 ml of tetrahydrofuran is added to a suspension of 81 mmol of LiAlH4 in 200 ml of tetrahydrofuran, maintained at 0C. After stirring for 12 hours at ambient temperature, the reaction mixture is hydrolysed using 2.75 ml of water, 2.2 ml of 20% sodium hydroxide solution and then 10 ml of water. After filtration and rinsing with tetrahydrofuran, the filtrate is dried and then concentrated under reduced pressure, allowing the expected product to be isolated.
The product is obtained according to the procedure of Preparation 17 using the product of Preparation 1 as substrate.
The product is obtained according to the procedure of Preparation 17 using the product of Preparation 3 as substrate.
The product is obtained according to the procedure of Preparation 17 using 4-(2-phenoxy-ethyl)piperidine as substrate.
The product is obtained according to the procedure described in Step 2 of Preparation 17 using {1-[3-(p-fluorophenoxy)propyl]-4-piperidyl}formamide as substrate and maintaining the reaction for 3 hours at reflux and then for 12 hours at ambient temperature.
The product is obtained according to the procedure of Preparation 7 using 1-bromo-2-(p-fluorophenoxy)ethane as substrate.
Step 1: 1,1-Bis(2-hydroxyethyl)-3-phenylurea
0.163 mol of diethanolamine dissolved in 160 ml of dichloromethane is added, at 10xc2x0 C., to a solution of 0.168 mol of phenyl isocyanate. After reacting for 1 hour at 10xc2x0 C. and then for 12 hours at ambient temperature, the reaction mixture is concentrated under reduced pressure.
Step 2: 1,1-Bis(2-chloroethyl)-3-phenylurea
26.44 ml of thionyl chloride are added, at 0xc2x0 C., to a solution of 0.173 mol of the product obtained in Step 1 in 100 ml of dichloromethane. After reacting for 4 hours at reflux and then for 12 hours at ambient temperature, the reaction mixture is concentrated under reduced pressure.
Step 3: 1-(2-Chloroethyl)-3-phenyl-2-imidazolidinone
0.167 mol of the product obtained in Step 2 is heated for 3 hours at 120xc2x0 C. and then for 6 hours at 140xc2x0 C. When no more gas is evolved, cooling is carried out. Chromatography over silica gel (dichloromethane) allows the expected product to be isolated.
Melting point (K): 92xc2x0 C.
The product is obtained according to the procedure of Preparation 23 using p-methoxyphenyl isocyanate in Step 1.
Melting point (K): 118xc2x0 C.
The product is obtained during purification of Preparation 24 over silica gel and is isolated in a ratio of 1:2.
Melting point (K): 171xc2x0 C.
The product is obtained according to the procedure of Preparation 23 using o-chlorophenyl isocyanate in Step 1.
The product is obtained according to the procedure of Preparation 23 using p-fluorophenyl isocyanate in Step 1.
Melting point (K): 105xc2x0 C.
The product is obtained according to the procedure of Preparation 23 using p-benzyloxyphenyl isocyanate in Step 1.
Melting point (M.K.): 128-133xc2x0 C.
The product is obtained according to the procedure of Preparation 23 using p-nitrophenyl isocyanate in Step 1.
Melting point (M.K.): 134xc2x0 C.
The product is obtained according to the procedure of Preparation 23 using p-chlorophenyl isocyanate in Step 1.
Melting point (M.K.): 112-114xc2x0 C.
The product is obtained according to the procedure of Preparation 1, Steps 1 and 2, using 2-(N-tert-butyloxycarbonyl-4-piperidyl)ethanol and p-chlorophenol as substrates.
Melting point of the hydrochloride (K.): 205xc2x0 C.
The product is obtained according to the procedure of Preparation 1, Steps 1 and 2, using p-methylthiophenol as substrate.
Melting point of the hydrochloride (M.K.): 206-210xc2x0 C.
The product is obtained according to the procedure of Preparation 1, Steps 1 and 2, using, as substrates, that of Preparation 2 and that of Preparation 32.
Melting point of the hydrochloride (M.K.): 146-150xc2x0 C.
The product is obtained according to the procedure of Preparation 1, Steps 1 and 2, using 2-(N-tert-butyloxycarbonyl-4-piperidyl)ethanol and phenol as substrates.
Melting point of the hydrochloride (K.): 155xc2x0 C.
The product is obtained according to the procedure of Preparation 23, Steps 1 to 3, using p-trifluoromethylphenyl isocyanate as substrate in Step 1.
Melting point (K.): 70xc2x0 C.
The product is obtained according to the procedure of Preparation 23, Steps 1 to 3, using p-cyanophenyl isocyanate as substrate in Step 1.
Melting point (K.): 149xc2x0 C.
The product is obtained in the form of an oil according to the procedure of Preparation 9 using the product of Preparation 17 as substrate.
Step 1: Phenylsulphlamoyl chloride
25.2 g of chlorosulphonic acid are added slowly to a solution of 60.6 g of aniline in 316 ml of methylene chloride cooled to xe2x88x925xc2x0 C. When the addition is complete, the mixture is allowed to return to ambient temperature and the precipitate obtained is filtered off. After drying, the precipitate is taken up in 231 ml of toluene, and 45.1 g of phosphorus pentachloride are added gradually. The mixture is then refluxed for 3 hours 30 minutes and, after returning to ambient temperature, the precipitate formed is filtered off. The filtrate is concentrated to obtain the expected product.
Step 2: N,N-bis(2-chloroethyl)-Nxe2x80x2-phenylsulphamide
66 g of the product obtained in Step 1 above are added to a suspension of 38.6 g of N,N-bis(2-chloroethyl)amine hydrochloride in 265 ml of xylene heated to 100xc2x0 C. The reaction mixture is heated at 140xc2x0 C. for 12 hours and, after cooling, filtered over a frit. The filtrate is concentrated and then purified by flash chromatography (eluant CH2Cl2/AcOEt: 95/5) to yield the expected product.
Step 3: 2-(2-Chloroethyl)-5-phenyl-1,2,5-thiadiazolidine-1,1-dioxide
Using a slow dropper, a solution of 12.6 g of the product obtained in Step 2 above in 25 ml of DMF is introduced onto a suspension of 1.4 g of NaH in 175 ml of DMF and stirring is carried out for 12 hours. The reaction mixture is then poured onto ice in order to bring about crystallisation of the expected product.
Melting point (K.): 45xc2x0 C.
The product is obtained according to the procedure of Preparation 38 using p-chloroaniline as substrate in Step 1.
Melting point (K.): 90xc2x0 C.
The product is obtained according to the procedure of Preparation 38 using p-fluoroaniline as substrate in Step 1.
Melting point (K.): 65xc2x0 C.
The product is obtained according to the procedure of Preparation 17 using, as substrate, 4-(p-methylthiophenoxymethyl)piperidine, which is obtained according to the procedure of Preparation 1 using, in Step 1, p-(methylthio)-phenol instead of p-fluorophenol.
Melting point (K.): 60-66xc2x0 C.
5 g of di-tert-butyl dicarbonate are introduced into a solution of 5 g of the product of Preparation 19 in 40 ml of methylene chloride and the mixture is stirred for 24 hours. After concentration in vacuo, the reaction mixture is purified by flash chromatography (eluant: CH2Cl2/EtOH: 95/5). The product obtained (5.5 g) is dissolved in 50 ml of THF and poured onto a suspension of 1.7 g lithium aluminium hydride in 70 ml of THF. The reaction mixture is refluxed for 7 hours and then, after cooling, hydrolysed at 5xc2x0 C. with, in succession, 11.7 ml of H2O, 6.1 ml of 20% sodium hydroxide solution and a further 6.7 ml of water. After filtration and concentration, the expected product is obtained.
The product is obtained in the form of an oil according to the procedure of Preparation 17 using the product of Preparation 13 as substrate in Step 1.
The product is obtained in the form of a colourless oil according to the procedure of Preparation 17 using the product of Preparation 15 as substrate in Step 1.
Step 1: 2-Methoxy-4-methyl-5-nitropyridine
22.3 g of 2-hydroxy-4-methyl-5-nitropyridine and 170 ml of POCl3 are mixed together and heated at 100xc2x0 C. for 3 hours. The cooled reaction medium is poured onto ice to yield a beige precipitate of 2-chloro-4-methyl-5-nitropyridine.
Melting point (M.K.): 38-39xc2x0 C.
10.95 g of sodium methanolate are added, in portions, to 5 g of the resulting precipitate dissolved in 110 ml of methanol. The reaction is exothermic and, when the addition is complete, the mixture is refluxed for 2 hours. After returning to ambient temperature, the reaction mixture is poured onto a mixture of 200 g of ice and 100 ml of water. The precipitate obtained corresponds to the expected product.
Melting point (M.K.): 80-84xc2x0 C.
Step 2: 5-Methoxy-1H-pyrrolo[2,3-c]pyridine
10.76 g of N,N-dimethylformamide dimethyl acetal and 2.45 ml of pyrrolidine are added, in succession, to a solution of 5 g of the product obtained in Step 1 in 60 ml of dimethylformamide. The mixture obtained is first heated at 100xc2x0 C. for 8 hours and then at 150xc2x0 C. for 1 hour. Concentration is carried out under a vacuum of 10xe2x88x921 mbar and the residue is taken up in 150 ml of tetrahydrofuran. The solution obtained is hydrogenated under a pressure of 10 bars for 4 hours in the presence of 10% Pd/C. After filtration and concentration, the residue is chromatographed over silica (eluant CH2Cl2/EtOH: 95/5) to yield the expected product.
Melting point (M.K.): 126-130xc2x0 C.